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Human Spermatogenic Failure Purges Deleterious Mutation Load from the Autosomes and Both Sex Chromosomes, Including the Gene DMRT1

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Human Spermatogenic Failure Purges Deleterious Mutation Load from the Autosomes and Both Sex Chromosomes, Including the Gene DMRT1 Human Spermatogenic Failure Purges Deleterious Mutation Load from the Autosomes and Both Sex Chromosomes, including the Gene DMRT1 Alexandra M. Lopes1.*, Kenneth I. Aston2., Emma Thompson3, Filipa Carvalho4, Joa˜o Gonc¸alves5, Ni Huang6, Rune Matthiesen1, Michiel J. Noordam6,Ine´s Quintela7, Avinash Ramu6, Catarina Seabra1, Amy B. Wilfert6, Juncheng Dai8, Jonathan M. Downie9, Susana Fernandes4, Xuejiang Guo10,11, Jiahao Sha10,11, Anto´ nio Amorim1,12, Alberto Barros4,13, Angel Carracedo7,14, Zhibin Hu8,10, Matthew E. Hurles15, Sergey Moskovtsev16,17, Carole Ober3,18, Darius A. Paduch19, Joshua D. Schiffman9,20,21, Peter N. Schlegel19,Ma´rio Sousa22, Douglas T. Carrell2,23,24, Donald F. Conrad6,25* 1 Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, 2 Andrology and IVF Laboratories, Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah, United States of America, 3 Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America, 4 Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal, 5 Department of Human Genetics, National Institute of Health Dr. Ricardo Jorge, Lisbon, Portugal, 6 Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America, 7 Genomics Medicine Group, National Genotyping Center, University of Santiago de Compostela, Santiago de Compostela, Spain, 8 Department of Epidemiology and Biostatistics and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China, 9 Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America, 10 State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China, 11 Department of Histology and Embryology, Nanjing Medical University, Nanjing, China, 12 Faculty of Sciences, University of Porto, Porto, Portugal, 13 Centre for Reproductive Genetics Alberto Barros, Porto, Portugal, 14 Galician Foundation of Genomic Medicine and University of Santiago de Compostela, CIBERER, Santiago de Compostela, Spain, 15 Genome Mutation and Genetic Disease Group, Wellcome Trust Sanger Institute, Cambridge, United Kingdom, 16 CReATe Fertility Center, University of Toronto, Toronto, Canada, 17 Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Canada, 18 Department of Obstetrics and Gynecology, University of Chicago, Chicago, Illinois, United States of America, 19 Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, New York, United States of America, 20 Center for Children’s Cancer Research (C3R), Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America, 21 Division of Pediatric Hematology/Oncology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America, 22 Laboratory of Cell Biology, UMIB, ICBAS, University of Porto, Porto, Portugal, 23 Department of Physiology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America, 24 Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America, 25 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America Abstract Gonadal failure, along with early pregnancy loss and perinatal death, may be an important filter that limits the propagation of harmful mutations in the human population. We hypothesized that men with spermatogenic impairment, a disease with unknown genetic architecture and a common cause of male infertility, are enriched for rare deleterious mutations compared to men with normal spermatogenesis. After assaying genomewide SNPs and CNVs in 323 Caucasian men with idiopathic spermatogenic impairment and more than 1,100 controls, we estimate that each rare autosomal deletion detected in our study multiplicatively changes a man’s risk of disease by 10% (OR 1.10 [1.04–1.16], p,261023), rare X-linked CNVs by 29%, (OR 1.29 [1.11–1.50], p,161023), and rare Y-linked duplications by 88% (OR 1.88 [1.13–3.13], p,0.03). By contrasting the properties of our case-specific CNVs with those of CNV callsets from cases of autism, schizophrenia, bipolar disorder, and intellectual disability, we propose that the CNV burden in spermatogenic impairment is distinct from the burden of large, dominant mutations described for neurodevelopmental disorders. We identified two patients with deletions of DMRT1, a gene on chromosome 9p24.3 orthologous to the putative sex determination locus of the avian ZW chromosome system. In an independent sample of Han Chinese men, we identified 3 more DMRT1 deletions in 979 cases of idiopathic azoospermia and none in 1,734 controls, and found none in an additional 4,519 controls from public databases. The combined results indicate that DMRT1 loss-of-function mutations are a risk factor and potential genetic cause of human spermatogenic failure (frequency of 0.38% in 1306 cases and 0% in 7,754 controls, p = 6.261025). Our study identifies other recurrent CNVs as potential causes of idiopathic azoospermia and generates hypotheses for directing future studies on the genetic basis of male infertility and IVF outcomes. Citation: Lopes AM, Aston KI, Thompson E, Carvalho F, Gonc¸alves J, et al. (2013) Human Spermatogenic Failure Purges Deleterious Mutation Load from the Autosomes and Both Sex Chromosomes, including the Gene DMRT1. PLoS Genet 9(3): e1003349. doi:10.1371/journal.pgen.1003349 Editor: Edward Hollox, University of Leicester, United Kingdom Received June 14, 2012; Accepted January 17, 2013; Published March 21, 2013 Copyright: ß 2013 Lopes et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was partially funded by the Portuguese Foundation for Science and Technology FCT/MCTES (PIDDAC) and co-financed by European funds (FEDER) through the COMPETE program, research grant PTDC/SAU-GMG/101229/2008. IPATIMUP is an Associate Laboratory of the Portuguese Ministry of Science, PLOS Genetics | www.plosgenetics.org 1 March 2013 | Volume 9 | Issue 3 | e1003349 Genetics of Spermatogenic Impairment Technology, and Higher Education and is partially supported by FCT. AML is the recipient of a postdoctoral fellowship from FCT (SFRH/BPD/73366/2010). CO is supported by a grant from the United States National Institutes of Health (R01 HD21244), JDS is supported by Damon Runyon Clinical Investigator Award, Alex’s Lemonade Stand Foundation Epidemiology Award, and the Eunice Kennedy Shriver Children’s Health Research Career Development Award NICHD 5K12HD001410. Support for humans studies and specimens were provided by the NIH/NIDDK George M. O’Brien Center for Kidney Disease Kidney Translational Research Core (P30DK079333) grant to Washington University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] (AML); [email protected] (DFC) . These authors contributed equally to this work. Introduction [14,15], type 2 diabetes [16], cardiovascular disease [17], and cancer [18,19,20,21]. Now, a role for CNVs in male infertility is Male infertility is a multifaceted disorder affecting nearly 5% of beginning to emerge [22,23,24,25]. men of reproductive age. In spite of its prevalence and a As a second approach to identify rare genetic variants, we use a considerable research effort over the past several decades, the population genetics modeling framework to identify large homo- underlying cause of male infertility is uncharacterized in up to half zygous-by-descent (HBD) chromosome segments that may harbor of all cases [1]. Some degree of spermatogenic impairment is recessive disease alleles. When applied to consanguineous families, present for most male infertility patients, and, in its most severe so-called ‘‘HBD-mapping’’ has been an unequivocal success in form, manifests as azoospermia, the lack of detectable spermato- identifying the location of causal variants for simple recessive zoa in semen, or oligozoospermia, defined by the World Health monogenic diseases [26]. HBD analysis can also be used to screen Organization as less than 15 million sperm/mL of semen. for the location of rare variants in common disease case-control Spermatogenesis is a complex multistep process that requires studies of unrelated individuals, using either a single-locus germ cells to (a) maintain a stable progenitor population through association testing framework or by testing for an autozygosity frequent mitotic divisions, (b) reduce ploidy of the spermatogonial burden, frequently referred to as ‘‘inbreeding depression’’: an progenitors from diploid to haploid through meiotic divisions, and enrichment of size or predicted functional impact of HBD regions (c) assume highly specialized sperm morphology and function aggregated across the genome. This approach has produced results through spermiogenesis. These steps involve the expression of for a growing list of common diseases, including
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